Unit-IV BP 502 T. (Industrial Pharmacy-I) Dr.

Bijay Kumar Sahoo

Syllabus
Parenteral Products:
1. Definition, types, advantages and limitations. Preformulation factors and essential requirements,
vehicles, additives, importance of isotonicity.
2. Production procedure, production facilities and controls, aseptic processing
3. Formulation of injections, sterile powders, large volume parenterals and lyophilized products.
4. Containers and closures selection, filling and sealing of ampoules, vials and infusion fluids.
Quality control tests of parenteral products
Ophthalmic Preparations:
Introduction, formulation considerations; formulation of eye drops, eye ointments and eye lotions;
methods of preparation; labeling, containers; evaluation of ophthalmic preparations.

Abbreviations: -

LVP: Large volume Parenteral

SVP: Small volume Parenteral

P: Partition coefficient

HEPA: High- efficiency Particulate Air

LAL Test: Limulus Amebocytes Lysate test

BET: Bacterial Endotoxin Test

IPC: In-Process Control

WFI: Water for Injection

RH: Relative Humidity

FTM: Fluid Thioglycolate Medium

SCM: Soyabean-casein digest Medium

1
1. Definition:
The term Parenteral has been derived from the Greek word Para enteron, which means
outside the intestine. These are unique dosage forms as they are administered by injecting directly
into the body tissues through skin and mucous membranes.
Parenteral products are sterile preparations containing one or more active ingredients
intended for administration by injection, infusion or implantation into the body. They are packaged
in either single-dose or multi dose containers.

Types Parenteral Products:

The types of Parenteral products are based on Volume and the state of product according to USP.
Based on Volume:
 SVP – An injection that is packed in containers labeled as containing 100 ml or less.
 LVP – These are parenterals designed to provide fluid, calories and electrolytes to the body
and the volume is more than 100ml.
Based on States of products:

 Injection: Injections contain sterile solutions and are prepared by dissolving the active
ingredient and other substances in Water for Injection or other suitable non-aqueous base or
a mixture of both. The solution to be injected may show sediments which can be dispersed
easily by shaking the container. The suspension should remain stable in order to deliver a
homogenous dose whenever withdrawal is made from the container.
 Infusions: These parenteral preparations are composed of sterile aqueous solution with
water as its continuous phase. The preparations are free from bacterial endotoxins or
pyrogens and are made isotonic with blood. They do not contain any antimicrobial
preservatives.
 Powder for Injection: These are sterile solid compounds that are distributed in their final
volume when the vial or container is shaken to form a clear particle-free solution.
 Concentrated Solutions for Injections: The concentrated solutions are diluted with water for
injection before they are administered through injection or through intravenous infusion.
 Implants: These solid sterile preparations are implanted in the tissue in order to release the
active ingredient for long periods. They are stored in sterile containers individually.
 Injectable Emulsion: These are liquid preparations in which the drug substances are
dissolved or dispersed in a suitable emulsion medium. These products provide essential fatty
acid and vitamins.
 Oily Injection: These are used to prepare parenteral controlled release dosage forms.

Advantages of Parenteral:
a) Parenteral products can By passes pre systemic or first pass metabolism and the Onset of
action is quick

2
 b) The drugs, which cannot be administered orally, can be administered by this route.
c) The patients who are vomiting or unconscious cannot take drug by oral route. In such cases,
the drug can be administered by this route.
d) The drug action can be prolonged by modifying the formulation.
e) This route can deliver transfusion fluids containing nutritives like glucose and electrolytes
such as sodium chloride.

Limitations:
a) Injection causes pain at the site of injection.
b) The trained persons are required to administer the drug.
c) The administration of drug through wrong route of injection may prove to be fatal.
d) It is difficult to save a patient when over dose is given.
e) There are chances of sensitivity reaction or allergic reaction of a drug by an individual. These
reactions are sometimes fatal and lead to death.

Preformulation factors and essential requirements:

Preformulation involves the study about physical & chemical properties of drug substance
prior formulation. These studies are performed under stressed conditions of temperature, humidity;
light and oxygen so that the reactions are accelerated and potential reaction are detected. A few
physicochemical properties that affect a drug substance are discussed below.
 Melting point: It is the Temperature at which the solid and liquid phases are in equilibrium.
Its determination is a primary indication of purity.
 Solubility: This property is essential for developing solution to be injected either
intraveneously or intramuscularly. It is a function of chemical structure: salts of acid or
bases are the drugs that can achieve the desired degree of water solubility.
 Molecular structure and weight: These are the basic characteristics of the drug from
which the potential properties and reactivities of functional groups can be determined.
 Particle Size and Shape: Study of particle size give information about Solubility,
dissolution rate and absorption etc.These charcterstics are determined by Scanning electron
microscope or an optical microscope with polarizing attachments.
 Ionisation constant: This property is used to determine the PH-dependent solubility of a
compound.Potentiometric PH titration or PH-solubility analysis is used for determining the
PKa value.Ionisation constant of a compound also helps in determining the degree of
ionization of an acid or base. Degree of ionization depends upon the PH.
For acidic drugs PKa ranges from 3-7.5 and for basic drugs PKa ranges from 7- 11.
 Partition Coefficient (P); It is a ratio of equilibrium concentration of drug in aqueous and
oily phases in contact with each other at a constant temperature. Partition coefficient can be
expressed as : P = [Coil / Cwater]],where, Coil= organic phase concentration and Cwater =
aqueous phase concentration.

3
  Hygroscopicity: The tendency of a solid to take up water from atmosphere, as it is
subjected to a controlled RH programe under isothermal condition. A high degree of
hygroscopicity can adversely affect the physical and chemical properties of a drug
substance.

Essential requirements for Formulation: The formulations of parenteral preparations need careful
planning, thorough knowledge of medicaments and additives to be used. The excess use of additives
in parenteral products should be avoided as some of these may interfere with the drug. In the
preparation of parental products, the following substances are added to make a stable preparation.
1. Vehicles
2. Additives
a) Solubilizing agents b) Stabilizers c)Buffering agents d) Antibacterial agents e) Chelating agents
f)Suspending ,emulsifying and wetting agents g)Tonicity factors

1. Vehicles:
There are two types of vehicles, which are commonly used for the preparation of injections
A) Aqueous vehicle - water is used as vehicle for majority of injections because water is tolerated
well by the body and is safest to administer .The aqueous vehicle used are ;-
1) Water for injections.
2) Water for injection free from CO2 (carbon dioxide)
3) Water for injection free from dissolved air, water for injection is sterile water, which is free from
volatile, non- volatile impurities and from pyrogens.
Pyrogens are by-product of bacterial metabolism. pyrogens are Lyposaccharide, thermostable,
soluble in water ,unaffected by bactericide and can pass through bacterial proof filters. pyrogens can
be removed from water by simple distillation process using an efficient trap which prevents the
pyrogen to enter into the condenser .immediately after the preparation of water for injection ,it is
filled in to the final container, sealed and sterilized by autoclaving .
Water for injection, contaminated with pyrogens may cause rise in body temperature if injected
.Hence, test for pyrogen is done to ensure that water for injection is free from pyrogens.
B) Non -aqueous vehicles:-The commonly used non-aqueous vehicles are oils and alcohols.
Fixed oil, such as arachis oil,cottonseed oil ,almond oil and sesame oil are used as vehicle .the oily
vehicles are generally used when a depot effect of drug is required or the medicaments are insoluble
or slightly soluble in water or the drug is soluble in oil example dimercaprol injection by using
arachis oil as vehicle.
Ethyl alcohol is used in the preparation of hydrocortisone injection .hydrocortisone is insoluble in
water, hence the solution is made in 50% alcohol .Alcohol causes pain and tissue damage at the site
of injection. Therefore, it is not used commonly.
Propylene glycol is used as a vehicle in the preparation of digoxin injection .it is relatively non-
toxic but it causes pain on S/C or I/M injection.

4
Sometime polyethylene glycol and glycerine usually diluted with sterile water are used to prepare
solutions for injections .they are used as solvent as well as to increase the stability of certain
preparations.
2. Additives:
These substances are added to increase the stability or quality of the product .These
additives should be used only when it is necessary to use them. While selecting the additives, care
must be taken that they should be compatible both physical and chemical with the entire
formulation, .They should be added in minimum possible quantity .The following additives are
commonly used in preparing stable parental preparations.
a) Solubilising agents:- These are used to increase the solubility of drugs which are slightly soluble
in water .the solubility of drug is increased by using surface active agent like tweens and
polysorbate or by using co solvents.
b) Stabilizers:- The drugs in the form of solution are more liable to deteriorate due to oxidation and
hydrolysis .The stabilizers are added in the formulation to prevent this .the oxidation can be
prevented by adding a suitable antioxidant such as, thiourea,ascorbic acid ,sodium metabisulphite
,or the product is sealed in an atmosphere of Nitrogen or Carbon dioxide. hydrolysis can be
prevented by using a non-aqueous vehicle or by adjusting the pH of the preparation.
Antioxidants:
Water soluble: Sulfurous acid salts, Ascorbic acid isomers, Thiol derivatives
Oil soluble; Propyl gallate ,Butylated hydroxyanisole ,Ascorbyl palmitate, alpha Tocopherol

c) Buffering agents: -The degradation of the preparation, which is due to change in pH, can be
prevented by adding a suitable buffer to maintain the desired PH .

pH Buffer system Concentration (%)

3.5-5.7 Acetic acid-acetate 1-2
2.5-6.0 Citric acid- citrate 1-5
6.0-8.2 Phosphoric acid- phosphate 0.8-2
8.2-10.2 Glutamic acid- glutamate 1-2

d) Antibacterial agents:- These substance are added in adequate quantity to prevent the growth of
microorganism during storage. so these substances act as preservatives .antibacterial agents
are added in single dose containers, where parenteral products are sterilized by filtration
method and in multi dose containers to prevent microbial contamination .
Some typical preservative used in parenteral suspensions and their commonly used
concentrations are as follows.-
Benzyl alcohol (0.9% to 1.5%)
Methylparaben (0.18% to 0.2%)
Propylparaben (0.02%)
Benzalkonium chloride (0.01% to 0.02%)
Thiomersal (0.001% to 0.01%)

5
f) Chelating agent: - Chelating agents such as EDTA (Ethylene diamine Tetra acetic acid) and its
salts, sodium or pottasium salts of citric acid are added in the formulation,to chelate the metallic
ions present in the formulation. They form a Complex which gets dissolved in the solvent.

S. No. Additives Concentration range (%)

1 EDTA disodium 0.00368-0.05

2 EDTA calcium disodium 0.04

3 EDTAtetrasodium 0.01

g) Suspending, emulsifying and wetting agents:- The suspending agents are used to improve the
viscosity and to suspend the particles for a long time. Methyl cellulose, carboxy-methyl
cellulose, gelatin and acacia are commonly used as suspending agents .Emulsifying agents are
used in sterile emulsions .for this purpose lecithin is generally used .The wetting agents are
used to reduce the interfacial tension between the solid particles and the liquid, so as to prevent
the formulation of lumps. They also act as antifoaming agents to subside the foam produced
during shaking of the preparation.
Additives Concentration range (%)
Polyethylene glycol 300 0.01-50.0
Polysorbate 20 0.01
Polysorbate 40 0.05
Polysorbate 80 0.04-4.0
Povidone 0.2-1.0
Propylene glycol 0.2-50.0
Sorbitan monopalminate 0.05
Dimethylacetamide 0.01
Lecithin 0.5-2.3

h) Tonicity factors: - Parenteral preparation should be isotonic with blood plasma or other body
fluids. The isotonicity of the solution may be adjusted by adding sodium chloride, dextrose
and boric acid etc. in suitable quantities. These substances should be compatible with other
ingredients of the formulation. Examples of Tonicity adjuster/modifier are Glycerin, lactose,
mannitol, dextrose, NaCl, sodium sulfate and sorbitol
Importance of Isotonicity:
An isotonic solution is one that exhibits the same effective osmotic pressure as blood
serum.Isotonicity is important for parenteral preparation because if the solution is isotonic with
blood, the possibility of product penetrating the RBC and causing haemolysis is reduced. For
hypertonic solution crenation and for hypotonic solution haemolysis will occur.

6
 Crenation Hemolysis

2. Production procedure - Aseptic processing:

• The parenteral drug manufacturing (Drug Product Manufacturing) process includes
compounding, mixing, filtration, filling, terminal sterilization, lyophilization, closing, and
sealing, sorting, and inspection, labeling, and final packaging for distribution.
• The manufacturing process is complicated; requiring organization and control to ensure the
product meets the quality and the specifications as shown in.
• Aseptic processing requirement adds more complication but assures that all dosage forms
manufactured are free from any contamination of microbial, endotoxin, and visible
particulate matter.
• The manufacturing process initiates with the procurement of approved raw materials (drug,
excipients, vehicles, etc.) and primary packaging materials (containers, closures, etc.) and
ends with the sterile product sealed in its dispensing package.

Process of Parenterals

The manufacturing of parenterals involves the following steps;

7
 1) Cleaning and washing of containers and closures
2) Preparation of solutions
3) Sterilization
4) Filling and sealing
5) Evaluation of parenterals
6) Packaging and labeling
1. Cleaning of containers and closures: - all the containers, closures and equipments which
are required during the preparation of parental products are thoroughly cleaned with
detergent and washing is done with tap water , followed by clean distilled water and finally
rinsed with water for injection. Rubber closures are washed with hot solution of 0.5 %
sodium pyrophosphate in water. The closures are then removed from the solution, washed
with water followed by rinsing with filtered water for injection .on a small scale washing is
done manually but on a large scale automatic washing machines are used.
2. Preparation of Solution:- The various ingredients of the formulation of parental
preparations are weighed and collected in the preparation room. the raw materials required
in the preparation of parenteral products should be pure. water for injection free from
pyrogens and microorganisms are used in preparation of parenteral products. The Industrial
pharmacist should decide the order of mixing and exact method of preparation to be
followed before preparing the parenteral products . The parenteral preparation must be
prepared under strict aseptic conditions . The ingredients are accurately weighed separately
and dissolved in the vehicle as per method of preparation to be followed. The parenteral
Solutions so formed is passed through bacteria proof filter ,such as ,filter candle, seitz filter,
membrane filter, and sintered glass filters. the primary objective of filtration is to clarify the
solution by removing foreign particles .if the parenteral preparations are required to be
sterilized by means of bacteria proof filters, filtration should be done under strict aceptic
condition to avoid contamination of filtered solution, before it is finally transferred into final
container and sealed
3. Sterilization:-The parental preparations should be immediately sterilized after sealing in its
final containers. The sterilization is done by any one of the methods of sterilization, which
depends on the nature of Medicaments present in the parenteral preparations.
For thermostable medicament ,the parenteral product are sterilised either by autoclaving at
the temperature of 115°C to 116°C for 30 minutes or 121 degree centigrade for 20 minutes
or in hot air oven at 160 degree centigrade for 2 hours. the thermolabile preparations are
sterilized by filtration through a suitable bacteria proof filters. parenteral preparations which
are sterilised by filtration method may contain a suitable bacteriostatic agent to prevent the
growth of microorganisms .When the solutions are used for intravenous or intrathecal
injection in doses exceeding 15 ml ,the bacteriostatic agent should not be used. The
sterilised product is filled into the final containers and sealed .the process of filtration, filling
and sealing are done under aseptic conditions.

8
 4. Filling and Sealing:- The filtered product is filled into final container such as, ampoules,
vials and transfusion bottles, which are previously cleaned and dried. ampoules are used for
feeling single dose whereas , vials are used for filling multidoses .bottles are meant for
filling transfusion fluids . On small scale feeling is done manually by using hypodermic
syringe and needle .on the large scale feeling is done by automatic filling machine.The
sterile Powders are filled into containers by individual weighing or by using automatic or
semi automatic devices. The filling operation is carried out under strict aseptic precautions.
During the filling of ampoules, the care should be taken that the solution should be filled
below the neck of ampoules and the solution should not touch the neck of ampoules. this
will prevent the cracking and stanining of the neck of ampoules at the time of Sealing.
Sealing should be done immediately after filling .Ampoules are sealed manually on a small
scale by rotating the neck of the ampoule in the flame of Bunsen burner but on a large scale
ampoule sealing machine is used in which tip of ampoule is used to fused to seal it . The
vials and transfusion bottles are sealed by closing its opening with rubber closures .The
rubber closures are held in place by crimping the aluminium caps which is done manually or
by mechanical means.
5. Evaluation of Parenterals:- The finished parenteral products are subjected to the following
test ,in order to maintain quality control.

a) Sterility test b) clarity test c) Leakage test d)Pyrogen test.

6. Packaging and labeling:- After evaluation of the parenteral preparation,the ampoules ,vials
and transfusion bottles are properly labelled and packed. The label should state as :-

a) Name of the preparation

b) Quantity of the preparation
c) Mfg.Lic .no.
d) Batch no.
e) Date of manufacture
f) Date of expiry
g) Storage condition
h) Retail price
i) Manufacturer's address

Production facilities and controls:

The production area where the parenteral preparations are manufactured can be divided into
the following five sections.
1) Clean-up area
2) Preparation area
3) Aseptic area
4) Quarantine area
5) Finishing & packaging area

9
 1. Clean-up area:
 It is not aseptic area.
 All the parenteral products must be free from foreign particles & microorganism.
 Clean-up area should be withstand moisture, dust & detergent.
 This area should be kept clean so that contaminants may not be carried out into
aseptic area.
2. Preparation area:
 In this area the ingredients of the parenteral preparation are mixed & preparation is
made for filling operation.
 It is not essentially aseptic area but strict precautions are required to prevent any
contamination from outside.

3. Aseptic area:
 The parenteral preparations are filtered, filled into final container & sealed in aseptic area.
 The entry of personnel into aseptic area should be limited & through an air lock.
 Ceiling, wall & floor of that area should be sealed & painted.
 The air in the aseptic area should be free from fibers, dust and microorganism.
 The High efficiency particulate air filters (HEPA) is used for air.
 UV lamps are fitted in order to maintain sterility.
4. Quarantine area:
 After filling, sealing & sterilization the parenteral product are held up in quarantine area.
 Randomly samples were kept for evaluation.
 The batch or product pass the evaluation tests are transfer in to finishing or packaging area.
5. Finishing & packaging area:
 Parenteral products are properly labelled and packed.
 Properly packing is essential to provide protection against physical damage.
 The labelled container should be packed in cardboard or plastic container.
 Ampoules should be packed in partitioned boxes

Controlled environment required for parenteral preparation:

10
 Clean Room Classified Areas: Due to the extremely high standards of cleanliness and purity
that must be met by parenteral products, it has become standard practice to prescribe specifications
for the environments (clean rooms) in which these products are manufactured. The Critical and
General area of clean room: The clean room divides into
1. Critical Area
2. General Area.
The critical area is the area around the point of the production where contamination can gain direct
access to the process. This area often protected by localized laminar flow clean benches and
workstations. The General area is the rest of the clean room where contamination will not gain
direct entry into the product but should be kept clean because of the transfer of contamination into
the critical area. It is necessary that the critical area be cleaned most often with the best cleaning
ability without introducing contamination.
Classification of Clean Rooms:-
The class is directly related to the number of particles per cubic foot of air equal to or
greater than 0.5 micron.
1. Class 100,000: Particle count not to exceed a total of 100,000 particles per cubic foot of a size
0.5μ and larger or 700 particles per foot of size 5.0μ and larger.
2. Class 10,000: Particle count not to exceed a total or 10,000 particles per cubic foot of a size 0.5μ
and larger or 65-70 particles per cubic foot of a size 5.0μ and larger.
3. Class 1,000: Particles count not to exceed a total of 1000 particles per cubic foot of a size 0.5μ
and larger or 10 particles per cubic foot of a size 5.0μ and larger.
4. Class 100: Particles count not to exceed a total of 100 particles per cubic foot of a size 0.5μ and
larger.
Class1: The particle count shall not exceed 3000 particles/m3 of a size 0.5μ.
Class 2: The particle count shall not exceed a total of 3000 particles/m3of a size of 0.5μ or greater;
2000 particles/m3of size 0.5μ or greater; 30 particles of a size 10μ.
Class 3: The particle count shall not exceed a total of 1,000,000 particles of a size of 1μ or greater;
20,000 particles/m3of size 5μ or greater; 4000 particles/m3of a size 10μ or greater; 300 particles of
a size of 25μ or greater.
Class 4: The particle count shall not exceed a total of 200,000 particles of a size of 5μ or greater.
For the manufacture of sterile medicinal products normally 4 grades can be distinguished:
GRADE ― ‘A’: The local zone for high risk operations. eg. filling zone, stopper bowls, open
ampules and vials. GRADE ― ‘B’: In case of aseptic preparation and filling, the back ground
environment for grade ― ‘A’ zone. GRADE ― ‘C’ & ‘D’: Clean areas for carrying out less critical
stages in the manufacture of sterile products.

Aseptic processing:-
The objective of aseptic processing is to maintain the sterility of a product that is assembled
from components, each of which, whenever possible products intended to be sterile should be
terminally sterilized by heat in their final container. Where it is not possible to carry out terminal

11
 sterilization by heating due to the instability of a formulation or incompatibility of a pack type
(necessary to the administration of the product, e.g. plastic eye-dropper bottles), a decision should
be taken to use an alternative method of terminal sterilization following filtration and/or aseptic
processing. Sterilization can be achieved by the use of moist or dry heat, by irradiation with
ionizing radiation (noting that ultraviolet irradiation is not normally an acceptable method of
sterilization), by ethylene oxide (or other suitable gaseous sterilizing agents), or by filtration with
subsequent aseptic filling of sterile final containers. In order to maintain the sterility of the
components and the product during aseptic processing, careful attention needs to be given to: the
environment, personnel, critical surfaces, container/closure sterilization and transfer procedures,
the maximum holding period of the product before filling into the final container and the
sterilizing filter. Certain solutions and liquids that cannot be sterilized in the final container can be
filtered through a sterile filter of nominal pore size 0.22 micron (or less), or with at least
equivalent microorganism-retaining properties, into a previously sterilized container. Such filters
can remove bacteria and moulds, but not all viruses or mycoplasmas. Consideration should be
given to complementing the filtration process with some degree of heat treatment. Filtration alone
is not considered sufficient when sterilization in the final container is possible. Of the methods
currently available, steam sterilization is preferred.

3. Formulation of injections (Solution and suspension):-

Solutions:
A range of excipients may be included in parenteral solutions, including antioxidants,
antimicrobial agents, buffers, chelating agents, inert gases, and substances for adjusting tonicity.
Antioxidants maintain product stability by being preferentially oxidized over the shelf life of the
product.
Antimicrobial preservatives inhibit the growth of any microbes that are accidentally introduced
while doses are being withdrawn from multiple-dose bottles and act as adjuncts in aseptic
processing of products.
It is Prepared by dissolving the drug and preservative, adjusting the pH and sterile- filtering the
resultant solution through a 0.22 μm membranes filter. Drug solutions that resist heat are terminally
autoclave sterilized after filling; this assures product sterility and package.

Suspension
A suspension for injection consists of insoluble solid particles dispersed in a liquid medium,
with the solid particles accounting for0.5-30% of the suspension. The vehicle may be aqueous, oil,
or both.
 Caking of injectable suspensions is minimized through the production of flocculated
systems, comprising clusters of particles (flocs) held together in a loose open structure.
 Excipients in injectable suspensions include antimicrobial preservatives, surfactants,
dispersing or suspending agents, and buffers.
 Surfactants wet the suspended powders and provide acceptable syringeability while
suspending agents modify the viscosity of the formulation.

12
 General steps in manufacturing:
 Sterilization and milling of active ingredient (s).
 Sterilization of vehicle.
 Aseptic wetting and dispersion of the active ingredient (s).
 Aseptic milling of the bulk suspension.
 Aseptic filling of the bulk suspension in suitable containers

Formulation of sterile powders:-

Due to instability in water, many drugs are formulated as drug powders to be reconstituted
prior to administration. eg.Penicillins, barbiturates, benzocain. Sterile water for injection is supplied
with dry powders to make “solutions / or suspensions for injections”. The obtained solution /
suspension will meet with all the requirements of solution /suspension for parenteral. IV or IM route
can give reconstituted solutions, however suspension is forbidden for IV administration.
Sterile powers are prepared by following methods.
1. Sterile recrystallization:
2. Lyophilization:
3. Spray drying
1. Sterile Re-crystallization: The drug is dissolved in a solvent and the obtained solution is
sterilized through 0.22 μm membrane filter. A sterile anti-solvent is then added to crystalize the
drug particles, which is filtered and dried aseptically.
Advantages:
This method is Flexible and economic.
Disadvantage:
This method represents variations from batch to batch and contamination.
2. Lyophilization: In this method, a solid substance is separated from solution by freezing the
solvent and evaporating the ice under vacuum. The obtained drug solution is sterile filtered into
sterile trays, which are aseptically loaded into a freeze dryer. The solution is then frozen at -50°C
and then dried by vacuum to separate the drug powder.
Advantage:
This method involves removal of water at low temperatures.
Disadvantage:
i) In this method, the biological molecules are damaged by the stress
associated with freezing, and drying.
ii) This method is expensive and time consuming

3. Spray drying: In this method, the solution of the drug is sprayed into a dry chamber where it
comes in contact with a hot steam of a sterile gas 80-100 °C temperature.

Advantage:
i) This method is Simple, Economical, scalable and faster.
ii) This method involves Coating of particles during drying prolonged release.
Disadvantage:

13
 i) In this method, the high processing temperatures and high shear forces can easily
damage drugs.
ii) In this method, higher levels of drugs are lost in comparison to freeze-drying.
iii) This method has a limited solvent choice for a given drug.
iv) In this method, product cannot be prepared directly in vials or plates.

Formulation of large volume parenterals: -

Large volume injections are intended to be administered by IV Infusion Fluids & are
included in the group of sterile products & are known as large volume Parenterals. These consist
of single dose injecting a volume of 100 ml or more than 100 ml sometimes additional drugs are
added to them by either injecting svp to the administration sets or by piggyback method(small
volume infusion of an additional drug is added to the intravenous delivery system).large volume
parenteral products include:
1) Infusion fluid(Basic nutrition -Dextrose inj, Fluid replacement therapy-Normal saline)
2) Total parenteral Nutrition solution(TPN)
3) Intravenous antibiotics
4) Dialysis fluid
5) Irrigation solutions
Large volume parenterals should be terminally heat sterilized. Apart from water for injection as the
main component, other ingredients that should be included are carbohydrates (e.g. dextrose, sucrose
and dextran), amino acids, lipid emulsion, electrolytes (Nacl) and glycerol, sorbitol and
mannitol.The LVP are mostly clear solutions, except for the oil- in –water emulsions. The
emulsions for infusion are produced by highly specialized method as they are destabilized by heat.
This result in many difficulties during production, thus the size of oil droplets should be controlled
during heat sterilization.

Production of LVP:
i) The manufacturing and filling of LVP fluids into containers are carried out in a a high
standard clean room environment. High standards are required to prevent these products from
getting contaminated with organisms, pyrogens and particulate matter.
ii) The fluids from a bulk container are filled into the product container using high speed filling
machine. Before filling the fluid into the container, it is passed through an in-line membrane
filter to remove the particulate matter.
iii) After filling, the neck of each glass bottle is immediately sealed with a tight fitting rubber
closure held in place with a crimped aluminum cap.
iv) In case plastic bags are used, the pre-formed plastic bags are aseptically filled and heat-sealed
immediately.
v) Blow –fill-seal system are adopted to minimizes the problems with product handling, cleaning
and particulate contamination.

14
 vi) The LVP products, including irrigation solution and dialysis fluids should be moist heat
sterilized immediately after the containers are filled.

Lyophilization or freeze-drying:-
Lyophilization or freeze drying is a process in which water is removed from a product after
it isfrozen and placed under a vacuum, allowing the ice to change directly from solid to vapor
without passing through a liquid phase. The process consists of three separate, unique, and
interdependent processes like; Freezing, Primary drying (sublimation), and Secondary drying
(desorption).
Advantages of Lyophilization
 Ease of processing a liquid, which simplifies aseptic handling.
 Enhanced stability of a dry powder.
 Removal of water without excessive heating of the product.
 Enhanced product stability in a dry state.
 Rapid and easy dissolution of reconstituted product
Disadvantages
 Increased handling and processing time.
 Need for sterile diluent upon reconstitution.
 Cost and complexity of equipment

Steps involved in formulation of Lyophilized products:-

 Dissolving the drug and excipients in a suitable solvent, generally water for injection
(WFI).
 Sterilizing the bulk solution by passing it through a 0.22-micron bacteria-retentive
filter.
 Filling into individual sterile containers and partially stoppering the containers under
aseptic conditions.
 Transporting the partially stoppered containers to the lyophilizer and loading into the
chamber under aseptic conditions.
 Freezing the solution by placing the partially stoppered containers on cooled shelves
in a freeze-drying chamber or pre-freezing in another chamber.
 Applying a vacuum to the chamber and heating the shelves in order to evaporate the
water from the frozen state.
 Complete stoppering of the vials usually by hydraulic or screw rod stoppering
mechanisms installed in the lyophilizers. There are many new parenteral products,
including anti-infectives, biotechnology derived products, and in-vitro diagnostics
which are manufactured as lyophilized products.

15
  Additionally, inspections have disclosed potency, sterility and stability problems
associated with the manufacture and control of lyophilized products

4. Selection of containers and closures:

Selection of Containers & Closures should be such that it should ensure that the products
must remain its purity, potency & quality during intimate contact with the container throughout its
shelf life.
Glass:-
Glass is employed as the container material of choice for most SVIs. It is composed,
principally, of silicon dioxide, with varying amounts of other oxides, such as sodium,
potassium, calcium, magnesium, aluminum, boron, and iron. Glass is preferred for clarity
reasons
Types:-
The USP provides a classification of glass:
• Type I, a borosilicate glass;
• Type II, a soda-lime treated glass;
• Type III, a soda-lime glass; and
• NP, a soda-lime glass not suitable for containers for parenteral.
Type I glass will be suitable for all products, although sulfur dioxide treatment is sometimes used
for even greater resistance to glass leach-ables. Because cost must be considered, one of
the other, less expensive types may be acceptable.
Type II glass may be suitable, for example, for a solution that is buffered, has a pH below 7, or is
not reactive with the glass.
Type III glass is usually suitable for anhydrous liquids or dry substances.
Types II and III glass compounds are composed of relatively high proportions of sodium oxide
(~14%) and calcium oxide (~8%). This makes the glass chemically less resistant. Both types melt at
a lower temperature, are easier to mold into various shapes.
Type II glass has a lower concentration of the migratory oxides than Type III. In addition, Type II
has been treated under controlled temperature and humidity conditions, with sulfur dioxide or other
de alkalizers to neutralize the interior surface of the container.
The glass types are determined from the results of two USP tests:
The Powdered Glass Test
The Water Attack Test.
The Powdered Glass Test challenges the leaching potential of the interior structure of the glass,
whereas the Water Attack Test challenges only the intact surface of the container.
Selecting the appropriate glass composition is a critical facet of determining the overall
specifications for each parenteral formulation. Glass can be the source / cause of leach-ables /
extractable, particulates (glass deamination or glass lamellae formation), adsorption of formulation
components, especially proteins, and cracks / scratches.
Plastic:-

16
 Plastic packaging has always been important for ophthalmic drug dosage forms and is
gaining in popularity for injectable dosage forms. Plastic bottles for large volume
injectable (LVIs) have been used for many years. Plastic vials for SVIs may be a wave of
the future plastic packing offers such advantages of cost savings elimination of the
problems caused by breakage of glass and increase convenience of use. Plastics are light
weight, less fragile & easy to handle but not clear as that of glass.
Rubber:-
Rubber formulations are used as rubber closures, rubber plungers and other applications.
The most common rubber polymers used in SVIs closures are natural and butyl rubber.
Silicone and neoprene also are used but less frequently in sterile products. Butyl rubber has
great advantages over natural rubber in that butyl rubber requires fewer additives, has low
water vapor permeation properties and has good characteristics with respect to gaseous
permeation reactivity with the active ingredient.
Rubber permits the entry of hypodermic needle into injection vials & also provide resealing
of the vial after needle is withdrawn.

Filling and Sealing of Ampoules:-

Ampoules are thin-walled glass containers, which after filling, are sealed by either tip
sealing or pull sealing. The contents are withdrawn after rupture of the glass, or a single occasion
only. These are great packaging for a variety of drugs. The filed – in product is in contact with glass
only and the packaging is 100% tamper proof. The break system OPC(one –point cut) or the color
break ring offer consistent breaking force. There are wide variety of ampoule types from 0.5 to
50ml volume.

• Here, the measured amounts of liquid deliver from the small orifice into the ampoule by filling
machine.
• The size of the delivery tube is governed by opening in the container to be used, the viscosity and
density of the liquid and the speed of delivery desired.
• The tube must free enter the neck of the container and deliver the liquid deep enough to permit air
to escape without sweeping the entering liquid into the neck or out of the container.
• Filling machine parts should be constructed of non-reactive materials such as borosilicate glass or
stainless steel.
• The solutions are usually filled in the bottle by gravity, pressure or vacuum filling device.
• Emulsion and suspension required specially designed filling equipment because of their high
viscosity.
• Powders such as antibiotics, are more difficult to subdivide accurately and precisely into
Individual dose containers than are liquid.
• Container should be sealed in the aseptic area in immediately adjacent to the filling machine.
• It is obvious that a sterile container that has been opened can no longer be considered to

17
 be sterile. Therefore, temperature proof sealing is essential.
• Ampoules may be closed by melting a portion of the glass of neck to either form tip-seals or pull
seals.
• Tip-seals are made by melting sufficient glass at the tip of the ampoule neck to form a bead of
glass and close the opening. This is performed in a high temperature gas oxygen flame.
• Pull-seals are made by heating the neck of a rotating ampoule below the tip, then pulling the tip
away to form a small, twisted capillary just prior to being melted closed. Pull sealing process is
slower one, but the sealing done by this is more secure than that of tip sealing.
• Excessive heating of air and gasses in the neck causes expansion against the soft glass with the
formation of fragile bubbles at the point of seal.

Filling and Sealing of Vials and Infusion bottle:-

The solutions, which sterilized through filtration, are to be filled under the aseptic
conditions. During the filling of product to the containers, should be for the prevention of
contamination, especially the product is sterilized by the filtration and will not be sterilized in to the
final container. The second one is called as aseptic fill. A liquid is more easily exposed uniformly
into the container having the narrow mouth than is used for solid. Liquids which are mobile are
easier to transfer and subdivide than viscous or sticky fluids, since these require heavy-duty
machinery for the rapid production filling. The filling of liquids into containers with high accuracy
involves the following methods
i) Volumetric filling
ii) Time/pressure filling
Volumetric filling machines have pistons or peristaltic pumps. These are most common used method.
Time-pressure filling is used for filling of sterile liquids. A filling system is connected by a
production tank that equipped with a pressure sensor. The sensor is used for the measurement of
pressure and transmits values PLC system that controls the product flow from the tank to the filling
manifold. The product is driven by using pressure mainly uses nitrogen with no pump mechanism.
By closing the opening using the rubber closure (stopper) the glass or the plastic vials are sealed
properly. This should be done by after filling with care, to prevent the contamination of the contents
inside. Increased chances for contamination are the large opening in the vials than the ampoules.
The open containers must be protected from contamination, especially with the blanket of HEPA
filtered laminar airflow. By using the aluminum caps the rubber stoppers are held in appropriate
place. Rubber closures that uses for the intravenous administration have a permanent hole through
the closure. A 500ml of infusion bottle is considered suitable for preparation of parenteral solutions.
It is assumed that the bottle has been stored with a double cap protecting the mouth. The outer cap
is discarded and the inner cap is removed. After ensuring that the bottle neck is not chipped, the
solution is poured in and immediately the inner cap is replaced.

18
Quality Control Tests of Parenteral Products:-
The following are the evaluation test for the parenteral. They are as follows.
1. Sterility test
2. Clarity test
3. Leakers test
4. Pyrogen test
1. Sterility test: It is a method carried out to detect confirm absence of any viable form of microbes
in product. The method used for sterility tests are
a. Direct transfer method
b. Membrane filtration method.
a. Direct transfer method: Open each sample container and with draw the require amount of the
sample. Inject one-half of sample in a test tube containing fluid Thioglycolate Medium (FTM).
Inject another half in the test tube containing Soyabean-casein digest Medium(SCM). Volume of
the medium must be sufficient to promote and expedite microbial growth. Adequate mixing
between the sample inoculums and the culture medium must take place to maximize interaction
and facilitate microbial growth. If the product to be tested contains any anti-microbial agent,
using suitable reagent it should be neutralized before the test.
b. Membrane filtration method (MF): This method is employed in the following cases:
1. Oil & oily preparations
2. Alcoholic preparations
3. For preparations miscible with or soluble in aqueous or oily solvents.
The steps involved in MF sterility test method are
i). The filter unit must be properly assembled and sterilized prior to use.
Ii). The contents are transferred to the filter assembly under strict aseptic conditions.
iii) The membrane is removed aseptically.
iv). Membrane is cut in half.
iv) One half is place in suitable volume of FTM and another in an equal volume of SCM.
Interpretation of results:
i). If there is no visible evidence of microbial growth, it may be interpreted that the sample is
without intrinsic contamination and the product complies the test for sterility.
ii). If microbial growth is found, the product does not complies the test for sterility and the sterility
test may be repeated.
2. Clarity test (particulate matter evaluation):-
Particulate matter in parenteral solutions has been recognized as an acceptable. Since the user
could be expected to conclude that the presence of visible dirt would suggest that, the product is
of inferior quality.
a). In visual method, the entire product should be inspected by human inspectors under good light
baffled against reflection into the eye and against black and white background. Dark background
detects light particles and light background detects dark particles. Any container with visible
particle if seen is discarded.

19
b). In Coulter counter method; the principle is based on that there will be an increase in the
resistance as a particle approaches and passes through the orifice (2 electrodes).
c). This method require destruction of the product unit since an electrolyte is added to the
preparation before its evaluation.
d). Some other methods of clarity testing can be listed as Filtration method, Light scattering
method, Light absorption, Light blockage methods, etc...
e). Once the particles are detected, then they are identified by various methods like microscopy,X-
ray powder diffraction, mass microscopy, micro-chemical tests, polarized light microscopy and
scanning electron microscopy.
3. Leakers test:-
Leaker test for ampoules is intended to detect incompletely sealed ampoules so that they can
be discarded in order to maintain sterile condition of the medicines. Open capillaries or cracks
at the point of seal result in LEAKERS.
 The leaker test is performed by immersing the ampoules in a dye solution, such as 1%
methylene blue, and applying at least 25 inches of vaccum for a minimum of 15 mins.
 Detection of leaker is prominent when ampoules are immersed in a bath of dye during
autoclaving as this has advantage of acomplishing both leaker detection and sterilization in one
operation.
 Another means of testing for leakers is a high frequency spark test system, which detect
presence of pinholes in ampoules.
 Bottles and vials are not subjected to such a vaccum test because of the flexibility of the rubber
closure.

4. Pyrogen test:-
Pyrogens are the metabolic products of microbes. Most bacteria, moulds and viruses
produce Pyrogen. Most potent pyrogenic substance called endotoxins are produced by gram
negative bacteria .Pyrogens when injected into a human, shows marked rise in the temperature ,
chills, body aches, cutaneous vasoconstriction and increased arterial blood pressure. The most likely
source of pyrogens are water, contaminated solutes and containers.
 The test involves measurement of the rise in body temperature of rabbits following the IV
injection of a sterile solution into ear vein of rabbit.
 Dose not exceeding 10 ml per kg injected intravenously within a period of not more than 10
mins.
 Selection of animals - healthy, adult, not less than 1.5kg.
 Equipment and material used in test - glassware, syringes, needles.
 Retaining boxes - comfortable for rabbits as possible.
 Thermometers - standardized position in rectum, precision of 0.1°C.
Preliminary Test (Sham Test):
If animals are used for the first time in a pyrogen test or have not been used during the 2
previous weeks, condition them 1 to 3 days before testing the substance by injecting IV 10ml per kg

20
pyrogen free saline solution warmed to about 38.5°c. Record the temperature of the animals,
beginning at least 90 mins before injection and continuing for 3 hours after injection. Any animal
showing a temperature variation of 0.6° or more must not be used in main test.
Main Test:
The main test is carried out by using a group of 3 Rabbits. Dissolve the substance in,or
dilute with, pyrogen free saline solution. Warm the liquid to approximately 38.5° before
injection.Inject the solution under examination slowly into the marginal veins of the ear of each
rabbit over a period not exceeding 4 mins. Record the temperature of each animal at half hourly
intervals for 3 hours after injection. The difference between the initial temperature and the
maximum temperature which is the highest temperature recorded for a rabbit is taken to be its
response.
Interpretation of Result:
a). The test is carried out on the first group of 3 rabbits; if necessary on further groups of 3 rabbits
to a total of 4 groups, depending on the results obtained.
b). Intervals of passing or failing of products are on the basis of summed temperature response.
If the difference is negative, the result is counted as zero response.
No. of Rabbits Individual Temp. Rise in Test
Temp. group (oC)
o
Rise( C)
3 Rabbits 0.6 1.4 Passes
(If above not 0.6 3.7 Passes
Passes)-:
3+5=8 Rabbits

If above Test not passes,the sample is said to Pyrogenic.

Bacterial Endotoxin Test (BET) or Limulus Amoebocyte Lysate Test (LAL Test):-

The bacterial endotoxin test (BET) is a test to detect or quantify endotoxins from gram
negative bacteria using Amoebocyte lysate from the horse shoe crab (Limulus polyphemus or
Tachypleustridentatus) .
The endotoxins of gram-negative bacteria forms a firm gel within 60 mins in the presence of lysate
of amebocytes of limulus polyphemus of horseshoe crab, when incubated at 37◦c. Hence, the test is
only effective with gram-negative bacteria, which constitute the majority and the most potent of the
pyrogens. The addition of a solution containing endotoxins to a solution of a lysate produces
turbidity, precipitation or gelation of the mixture.

21
Ophthalmic Preparations:-

Introduction;
Ophthalmic preparations (eye preparations) are sterile, liquid, semisolid, or solid
preparations that may contain one or more active pharmaceutical ingredient(s) intended for
application to the conjunctiva, the conjunctival sac or the eyelids. The choice of base and any
excipients used for the preparation of ophthalmic preparations must be proven through product
development studies not to affect adversely either the stability of the final product or the availability
of the active ingredients at the site of action. The most commonly employed ophthalmic dosage
forms are solutions, suspensions, and ointments. But these preparations when instilled into the eye
are rapidly drained away from the ocular cavity due to tear flow and lachrymal nasal drainage.
Eye is the most easily accessible site for topical administration of a medication. Ideal ophthalmic
drug delivery must be able to sustain the drug release and to remain in the vicinity of front of the
eye for prolong period. The newest dosage forms for ophthalmic drug delivery are: gels, gel-
forming solutions, ocular inserts, intravitreal injections and implants.

Anatomy of the human eye.

Formulation considerations:-
a) Tonicity and Tonicity-Adjusting Agents: The tonicity of aopthalmic solution should be
adjust correctly(urge a osmotic pressure equal to that of tear fluids, generaly agreed to be
equal to 0.9% NaCl) a range of 0.5-2.0% NaCl equvivalency does not cause a marked pain
and range of about 0.2-0.7% sholud be acceptable for most persons. Common tonicity
adjusting ingridient are:NaCl, Kcl, Buffer salt, dextrose, glycerine, propylene glycol and
mannitol.
b) pH Adjustment and Buffers: pH adjustment is very important as pH affects:
 To render the formulation more stable
 The comfort, safety and activity of the product. Eye irritation→ increase in tear fluid
secretion→Rapid loss of medication
 To enhance aqueous solubility of the drug.
22
  To enhance the drug bioavailability
 To maximize preservative efficacy Ideally every product buffered to a pH of 7.4(The
normal physiological pH of tear fluid) If buffers are required, their capacity is controlled
to be as low as possible.
 To enable the tears to bring the pH of the eye back to the physiological range
 To avoid effect of buffers on tonicity. Examples of buffer vehicles used:-Boric acid
vehicle: pH ofslightly below 5-Isotonic phosphate vehicle: pH ranges from 5.9 -8.
c) Viscosity-Imparting Agents:
Polyvinyl alcohol, methylcellulose, hydroxyl propyl methylcellulose, hydroxylethylcellulose
and carbomers are generally used in parentral preparation as viscosity imparting agent. They
increase the ocular contact time thereby they decrease the drainage rate, increase the
mucoadhessiveness and increase drug bioavilability.
d) Stabilizers & Antioxidants:
Stabilizers are the ingredients, which makes the preparation to decrease the rate of
decomposition of active ingredient. Antioxidants are principle stabilizers added to some
opthalmic preparation, primarily those containing epinephrine, and other oxidizable
drugs.Example: Sodium bisulphite or metabisulphite are used in concentration up to 0.3% in
epinephrine hydrochloride and bitartrate solution.
e) Surfactants:
The order of surfactant toxicity is anionic>cationic>>non-ionic. There are several non-ionic
surfactant are used in low concentration to add in dispersing steroid in suspensions and to
achieve or improve solution clarity. Some of the surfactant which are principally used are
sorbiton ether esters of oleic acid (polysorbate or tween 20 and 80).
f) Preservatives:
Preservatives are included in multiple-dose eye solutions for maintaining the product
sterility during use. Preservatives not included in unit-dose package. The use of
preservatives is prohibited in ophthalmic products that are used at the of eye surgery
because, if sufficient
concentration of the preservative is contacted with the corneal endothelium; the cells can
become damaged causing clouding of the cornea and possible loss of vision. The most
common organism is Pseudomonas aeruginosa that grow in the cornea and cause loss of
vision. Examples: benzalkonium chloride, 0.004% to 0.01%;benzethonium chloride, 0.01%;
chlorobutanol,0.5%; phenylmercuric acetate, 0.004%; phenylmercuric nitrite, 0.004%; and,
thimerosal, 0.005%to 0.01%.

Formulation of eye drops:

Ophthalmic solutions are sterile solutions intended for instillation in the eye.In addition to
sterility, these dosage forms require the careful consideration of such other pharmaceutical
factors as the need for antimicrobial agents, osmolarity, buffering, viscosity, and proper
packaging.

23
 An eye drop formulation comprises of the following:
a) Active ingredients to produce desired therapeutic effect.
b) Vehicle(Aquous or Oily).
c) Inert antimicrobial preservatives to prevent microbial contamination and to maintain sterility.
d) Inert adjuvants for adjusting tonicity, Viscosity and PH to increase the stability of active
ingredients.
e) Suitable container to maintain the preparation in a stable form and provide protection against
contamination during preparation, storage and use.
f) Multi dose eye drops are added with an effective antimicrobial preservative system(a single
substance cannot be successfully used as a preservative in ophthalmic solution) that should
pass the test for efficacy of antimicrobial preservative. This ensures that the eye drops are
sterile and non-contaminated.

Formulation of Eye Ointments:

Ophthalmic ointments must be sterile. Like suspensions, ointments can be more difficult to
manufacture in sterile form. They can be terminally sterilized, or, alternatively, they must be
manufactured from sterile ingredients in an aseptic environment. Filtration through a suitable
membrane or dry heat sterilization is often used.
 The ointment base selected for an ophthalmic ointment must be non-irritating to the eye and
must permit the diffusion of the active ingredient throughout the secretions bathing the eye.
 Ointment bases utilized for ophthalmics have a melting or softening point close to body
temperature.
 Ophthalmic ointments have a longer ocular contact time when compared to many
ophthalmic solutions.
 Ointment base is sterilized by heat and filtered while molten to remove foreign particulate
matter.
 It is then placed into a sterile steam jacketed to maintain the ointment in a molten state and
excipients are added.
 One disadvantage to ophthalmic ointments is the blurred vision that occurs as the ointment
base melts and spread across the lens.
 The bases like; yellow soft paraffin, liquid paraffin and wool fat can be used for the
preparation of eye ointment.

Formulation of Eye Lotions:-

Eye lotions are undiluted aqueous solutions, applied to an eye bath, which for first aid
purposes. It is may allow a large volume of fluid to flow quickly over the eye.
It is iso-osmotic to tears, because compared to eye drops, lotions cause much greater dilution of
the lachrymal fluid, hence cause discomfort if not adjusted.e.g. Sodium chloride (NaCl) eye lotion
B.P.C. is used to remove foreign substance from the eye.

24
 Thus these preparations should be very simple as well as the most common eye lotion consists of
sterile normal saline. This preparation demonstrate the requirements of an eye lotion which are:
 Sterile as well as usually containing no preservative.
 Isotonic to lachrymal fluid
 Natural pH
 Large volume but not greater than 200ml
 Non-irritant to ocular tissue.

Methods of Preparation:
1) Preparation of the Solution: The aqueous eye drops vehicle containing suitable preservative
, antioxidant , stabilizer, tonicity modifier , viscosity modifier, or buffer should be
prepared, and added with the active ingredient and the vehicle to make up the volume.
2) Clarification: sintered glass filters or membrane filters having 0.45-1.2 µm pore sizes
should be used. The clarified solution is either fillied directly into the final containers
which are sealed before heat sterilisation or is temporarily filled into a suitable
container before filtration. Clarified containers vehicle is used to prepare eye drop
suspensions filled into final containers and sealed before sterilisation.
3) Sterilisation: This can be achieved by autoclaving at 115oC temperature for 30 minutes or
121oC temperature for 15 minutes . Filtration into sterile containers through a membrane
filter having 0.22µm pore size is also a suitable method for sterililisation.Dry heat sterilisation
at 160oC temperature for 2 hours is best suited for non-aqueous preparations such as liquid
paraffin eye drops.
4) After sterilisation, the eye drop containers should be covered with a readily breakable seal to
distinguish between opened and unopened containers.

Labeling:-
The label should include:
(1) The name of the pharmaceutical product;
(2) The name(s) of the active ingredient(s); International Nonproprietary Names (INN) should be
used wherever possible;
(3) The concentration(s) of the active ingredient(s) and the amount or the volume of preparation in
the container;
(4) The batch (lot) number assigned by the manufacturer;
(5) The expiry date, the utilization period, and, when required, the date of manufacture;
(6) Any special storage conditions or handling precautions that may be necessary;
(7) If applicable, the period of use after opening the container;
(8) Directions for use, warnings and precautions that may be necessary;
(9) The name and address of the manufacturer or the person responsible for placing the product on
the market;

25
(10) If applicable, the name(s) and concentration(s) of antimicrobial agent(s) and/or antioxidant(s)
incorporated in the preparation; and
(11) The statement "This preparation is sterile".

Storage:
Ophthalmic preparations should maintain their integrity throughout their shelf-life when
stored at the temperature indicated on the label. Special storage recommendations or limitations are
indicated in individual monographs.

Containers:
Traditionally, ophthalmic liquid products were packed in glass containers fitted with an eye
dropper. Today, glass containers have limited use where product stability or compatibility issues
exclude the use of flexible plastic containers made of polyethylene or polypropylene. Most liquid
ophthalmic products on the market are packaged in plastic containers fitted with nozzles from
which, by gentle squeezing, the contents may be delivered as drops.
 Plastic containers have several advantages over the glass-dropper combination such as
minimizing the risk of the contents being contaminated with microorganisms by the
replacement of the dropper which may have become contaminated by touching the infected
eye or any other surfaces. Also, plastic containers are cheap, light in weight, more robust to
handle and easier to use than glass-dropper type containers.
 Some plastic materials such as polyethylene can absorb some antimicrobial preservatives
(e.g. benzalkonium chloride), or some drugs. They may also leach plasticizers into the
product, or printing inks from the label can migrate through the plastic into the product.
 The challenge is to develop a packaging system for preservative-free products that maintains
the sterility of the product throughout its shelf-life and during use.
 Unit-dose systems offer the easiest technical solution to this problem but have the
disadvantage of higher cost of manufacture and of not being as compact as a multidose
product containing equivalent doses.
 An alternative approach is to develop a multidose preservative free system. The container is
required to be collapsible, and the suck-back of air, which could contain bacteria, has to be
avoided. Containers are being developed that contain a valve mechanism to achieve this
 Plastic containers can also be permeable to water vapor and oxygen over prolonged periods
of storage. This can lead to gradual loss of liquid product or oxidation of an unstable drug
over time.
 Polyethylene containers are not able to withstand autoclaving and are usually sterilized by
ethylene oxide or by irradiation before being filled aseptically with pre-sterilized product.
Polypropylene containers can be autoclaved, but are not as flexible as polyethylene for
eyedropper use.

26
  Semi-solid products have been traditionally packed in collapsible tin tubes. Metal tubes are a
potential source of metal particles in ophthalmic products, and so the tubes have to be
cleaned carefully prior to sterilization.
 Collapsible tubes made from laminates of plastic, aluminum foil and paper are good
alternative to tin tubes. Laminate tubes fitted with polypropylene caps can be sterilized by
autoclaving.

Evaluation of ophthalmic preparations:-

Ophthalmic preparations are evaluated as follows:

1) Sterility: The ophthalmic products should meet the standard requirements. If the ingredients
used do not lend themselves to routine sterilization, ingredients that meet the sterility
requirements should be used. The container for ophthalmic preparations should be sterilized
at the time of filing and closing. They should be sealed and tamper-proof to maintain their
sterility.
2) Antimicrobial preservatives: These should be added to multiple-dose containers, unless there
are different directions provided in the individual monograph for multiple product
withdrawal, the substance contains a radionuclide with a physical half of less than 24hours,
he product itself is sufficiently microbicidal, or the added ingredients meet the requirements
of antimicrobial agent content. Thus, acceptance criteria for the content of antimicrobial
preservative in multiple-unit products should be established.
3) Uniformity of Dosage Units: This test should be performed for single-dose containers to
evaluate the mass of dosage form as well as the content of the drug substance(s) in the
dosages form. The test is performed by either content uniformity or weight variation.
4) Uniformity in Containers: Semisolid drug products undergo physical separation during
manufacturing and /or during the storage period. To ensure the drug product integrity, the
uniformity of the finished product at the time of batch release and throughout its shelf-life
should be evaluated.
5) Leachable and Extractables: The packaging system and the preparation should not undergo
any physical or chemical interaction to alter the strength, quality, or purity of the drug
product. The packaging system should meet the requirements in elastomeric closures for
injection, and glass or plastic containers.
6) Container Closure Integrity: The packaging system should be closed or sealed to prevent
contamination or loss of contents. It should also be tamper-proof. Validation of container
integrity should demonstrate no penetration of microbial, chemical or physical
contaminants.

27
 7) Viscosity: The residence time of the product in eyes increases in viscosity; but the diffusion
of drug from the formulation in to the eye is inhibited. The ophthalmic ointments have a
very high viscosity to prolong their residence time in the eyes.
8) Antioxidant Content: The content of antioxidants ( if added in the drug product) should be
established unless oxidative degradation can be detected by another test method such as
impurity testing. Acceptance criteria for antioxidant content should also be established based
on the levels of antioxidant required to keep the product stable throughout its shelf-life.
9) Particle Size and Particle Size Distribution: The potential for any changes in the particle size
of ophthalmic suspensions and emulsions should be evaluated through stability testing. the
drop size for ophthalmic drops ranges from 20-70µm.However,the drop size should be
controlled and maintained throughout the product shelf-life. Suitable substances should be
added to the ophthalmic products to increase their stability, provided they do not cause any
harm in the amounts administered and do not interfere with the therapeutic efficacy or
responses to the specified assays and tests.

References:

1) Introduction to Pharmaceutical Dosage Forms. Ansel, HC— 4th ed. Philadelphia: Lea &
Febiger; 1985:321–336.
2) Industrial pharmacy-I by KL Senthilkumar, AS Mundada and RS Kankate: Ist ed.Thakur
Publication, pg. no.163-204.
3) Pharmaceutical dosage forms: parenteral medications of industrial pharmacy, Lachmann/
Lieberman's, 4th edition, pg.no. 864-871.
4). Dispensing pharmacy by R M Mehta, pg.no. 303-311.
5). The science & practice of pharmacy, Remington, 21st edition, pg.no. 1367-1374.

28